We propose to carry out a program of research aimed at (1) the elucidation of the biochemical mechanisms of malignant transformation, (2) the elucidation of the mechanisms regulating the expression of malignancy and differentiation, and (3) the determination of the alterations leading to resistance to toxic base analogues in mammalian cells. The studies on malignant transformation will utilize a line of "bromodeoxyuridine" cells that we have isolated from a Syrian hamster melanoma line. The BUDR dependent cells require high concentrations of BUDR for the continued expression of characteristics associated with transformation in vitro. The studies of the regulation of malignancy and differentiation will focus on the question - is the suppression of malignancy and differentiation by BUDR due to the presence of the analogue in DNA? The studies on resistance to toxic analogues will be based on a line of cells that we have selected for the ability to survive with all the thymidine residues in nuclear DNA replaced by BUDR. The experiments will involve the techniques of membrane analysis, enzyme assay, nucleotide analysis, and cell culture.